JP2008516251A - マイクロ流体制御による区画化されたスクリーニング - Google Patents
マイクロ流体制御による区画化されたスクリーニング Download PDFInfo
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Abstract
Description
(a) それらは、各々がほとんど同一のきわめて小さいマイクロ反応装置として機能する、きわめて単分散のマイクロカプセル(1.5%未満の多分散性)の形成を可能にする。
(b) マイクロカプセルは、約1フェムトリットル〜約ナノリットルの範囲の体積を有することができる。
(c) マイクロカプセル内の区画化が、放物流に起因する拡散および分散を妨害する。
(d) ペルフルオロカーボン担体流を使用することにより、マイクロカプセル間の分子の交換を妨げることが可能である。
(e) マイクロカプセル内の化合物は、不活性ペルフルオロカーボン担体流体の層により分離されることから、マイクロチャンネルの構造と反応することも相互作用することもできない。
(f) マイクロカプセルを10,000秒−1以下で作り出すことができ、又、同じ速度で光学的方法を用いてスクリーニングできる。これは一日最高109の処理量である。
(g) マイクロカプセルを2つ以上のより小さいマイクロ液滴に分割でき、その中に含まれた試薬を並行して異なる一連の分子と反応させるかまたはマルチプリケートで検定することを可能にする。
(h) マイクロカプセルを融合させることができる。こうして分子を(a)希釈させ、(b)その他の分子と混合物させ、(c)精確に定義された時刻に反応を開始、終結または変調させることができる。
(i) カオス的移流を用いてマイクロカプセル内で非常に急速に試薬を混合させることができ(2ms未満)、高速運動測定および非常に高い処理量を可能にする。
(j) 組合せ式に試薬を混合させることができ、例えば、テストすべき標的に対する化合物ライブラリ内の化合物の考えられる全ての対様組合せの効果を可能にする。
(k) マイクロカプセルの安定流をマイクロチャンネル状に形成し、その相対的位置により同定することができる。
(l) 反応に光シグナル(例えば蛍光変化)にが随伴する場合、マイクロ流体ネットワークの空間分解された光学画像が各々のマイクロカプセル内の反応の時間分解測定を可能にする。
(m) マイクロカプセルは、それに含まれる分子の回収およびさらなる分析または操作を可能にするべくマイクロ流体流選別装置を用いて分離可能である。
a) レパートリの1サブセットのみが、任意のマイクロカプセル内において多重コピーで代表されるような形で、化合物をマイクロカプセルに区画化する工程;および
b) 所望の活性を有する化合物を同定する工程、
を含み、工程a)およびb)のうちの一方または両方が流体種のマイクロ流体制御下で実施される方法が提供されている。
(a) レパートリの1サブセットのみがいずれか1つのマイクロビーズ上で代表されるような形で、マイクロビーズ上に化合物のレパートリを付着させる工程、
(b) マイクロビーズをマイクロカプセルに区画化させる工程、
を含み、かくして任意の1つのマイクロカプセル内において多重コピーで該レパートリの1サブセットが代表されることになるように修飾される。
(a) レパートリの1サブセットのみが任意の1マイクロビーズ上で代表されるような形で、化合物レパートリをマイクロビーズ上に付着させる工程;
(b) マイクロビーズをマイクロカプセルに区画化する工程、
(c) 任意には、マイクロビーズから化合物を放出する工程;および
(d) 所望の活性を有する化合物を同定する工程、
を含み、工程a)およびb)の一方または両方が流体種のマイクロ流体制御下で実施される方法が提供されている。
(I) 第1の実施形態においては、マイクロカプセルは、マイクロカプセルを全体として検出可能にする化合物またはその誘導体の活性に従ってスクリーニングされる。従って、本発明は、所望の活性をもつ化合物が、その化合物を含むマイクロカプセルの同定を可能にするマイクロカプセル内の変化またはマイクロカプセル内部の1つ以上の分子の修飾を誘発している方法を提供している。従って、この実施形態では、該マイクロカプセルは、(a)中に含まれている化合物の活性に従って互いに物理的に選別され、選別されたマイクロカプセルの中味が任意に1つ以上の共通区画内にプールされ、マイクロカプセルの中味が、該化合物の同一性を判定するべく分析されるか;または(b)該マイクロカプセルに入っている化合物の同一性を判定するべく選別なしで直接分析されるかのいずれかである。マイクロカプセルがマイクロビーズを含有する場合、マイクロビーズを分析してそれらをコーティングしている化合物を判定することができる。
本明細書で使用される「または」という用語は、「包含的にまたは」、すなわち、多くの要素の2つ以上または要素のリストの2つ以上を含めた少なくとも1つの包含を意味するものとして理解されるべきである。これとは対照的に、「排他的にまたは」という用語は、多くの要素の正確に1つの要素または要素のリストのうちの正確に1つの要素の包含を意味する。
別段の定義のないかぎり、本明細書で使用されている全ての技術的および科学的用語は、(例えば細胞培養、分子遺伝学、核酸化学、ハイブリダイゼーション技術および生化学などにおいて)当業者により一般に理解されるものと同じ意味を有する。分子、遺伝子および生化学的方法(一般に、本明細書に参照により援用されているサンブルック(Sambrook)ら、「Molecular Cloning:A Laboratory Manual」、第2版(1989年)、Cold Spring Harbor Laboratory Press、Cold Spring Harbor、N.Y.およびアウスベル(Ausubel)ら、Short Protocols in Molecular Biology(1999年)第4版、John Wiley & Sons、Inc.を参照のこと)および化学的方法については、標準的方法が使用される。さらに、標準的な免疫学的技術のためには、ハーロウ(Harlow)およびレーン(Lane)、A Laboratory Manual Cold Spring Harbor、N.Yが参照される。
本発明のマイクロカプセルは、本発明の機能を可能にするべく適切な物理的特性を必要とする。
(a) それらは、各々がほぼ同一の非常に小さい超小型反応器として機能する高単分散性のマイクロカプセル(<?1.5%未満の多分散性)の形成を可能する、b)マイクロカプセルは約1フェムトリットルから約1ナノリットルの範囲の体積を有することが可能である、c)マイクロカプセルの区画化は放物線流に起因する拡散および分散を防止する。
(b) ペルフルオロカーボン担体流体を用いることにより、マイクロカプセル間の分子交換を防止することが可能である。
(c) マイクロカプセル内の化合物は、不活性ペルフルオロカーボン担体流体層により分離されるためマイクロチャンネルの構造と反応または相互作用できない。
(d) マイクロカプセルを10,000秒−1以下で作り出し、かつ同じ速度で光学的方法を用いてスクリーニングされ得る。これは一日あたり最高109の処理量である。
(a) マイクロカプセルは2つ以上のより小さいマイクロ液滴に分割され得、かくして中に含まれた試薬を並行して一連の異なる分子と反応させるかまたは多系(multiplicate)で検定することができるようにする。
(b) マイクロカプセルを融合することができる。こうして、分子は(a)希釈され得、(b)その他の分子と混合され得、かつ(c)反応が精確に定義された時刻に開始、終結または変調され得ることになる。
(c) カオス的移流を用いてマイクロカプセル内できわめて迅速に(2ms未満で)試薬を混合でき、かくして高速の反応速度測定および非常に高い処理量が可能となる。
(d) 試薬を組合せにより混合できる。例えば、テストすべき標的に対する、化合物ライブラリ内の化合物の考えられる全ての対様の組合せの効果を可能にする。
(a) マイクロカプセルの安定流をマイクロチャンネル内に形成し、その相対的位置により同定することができる。
(b) 反応に光シグナル(例えば蛍光変化)が随伴する場合、マイクロ流体ネットワークの空間的に分解された光学的画像が、各マイクロカプセル内の反応の時間分解測定を可能にする。
(c) マイクロカプセルが含む分子の回収およびさらなる分析または操作を可能にするべくマイクロ流体フロー選別装置を用いてマイクロカプセルを分離することができる。
さらにもう1つの態様においては、本発明は、一部のケースでは液体中の流体液滴を比較的高い速度でスクリーニングまたは選別するためのシステムおよび方法を提供している。例えば、液滴の特性を検知しかつ/または何らかの形で(例えば以下で詳述する通り)判定することができ、その後該液滴を、例えば選別またはスクリーニングを目的としてデバイスの特定の領域に向かって導くことができる。
標的に結合するかまたはその活性を変調させる化合物をスクリーニングするために、1つ以上の化合物または化合物でコーティングされたマイクロビーズと共にマイクロカプセルに標的を区画化する。有利には、各々のマイクロカプセルは単一種の化合物のみ、ただしその数多くのコピーを含んでいる。有利には、各々のマイクロビーズは単一種の化合物のみ、ただしその数多くのコピーでコーティングされている。有利には、化合物は、開裂可能なリンカーを介してマイクロビーズに連結され、それらが区画内でマイクロビーズから放出され得るようにしている。有利には、各々のマイクロカプセルまたはマイクロビーズは、マイクロカプセル内の含まれたまたはマイクロビーズに付着した化合物の同定を可能にするべく、光学的にタグ付けされている。
標的に対する結合について、直接化合物をスクリーニングすることができる。この実施形態においては、該化合物がマイクロビーズに付着されかつ標的に対する親和性を有する場合、それは標的による結合を受けることになる。反応の終りで、全てのマイクロカプセルは組合わされ、全てのマイクロビーズは1つの環境内で一緒にプールされる。標的に特異的に結合するかまたは標的と特異的に反応する分子を用いた親和性精製により、所望の結合を示す化合物を担持するマイクロビーズを選択することができる。
(1) 化合物自体は、例えば蛍光性であるといった独特の光学特性を有する可能性がある。
(2) 例えば化合物の蛍光を結合時点で消光または増強させるといったように、標的に対する結合時点で化合物の光学特性を修飾させることができる(ヴォス(Voss)、1993年;増井および倉光、1998年)。
(3) 例えば標的の蛍光を結合時点で消光または増強させるといったように、化合物の結合時点で、標的の光学特性を修飾させることができる(ギシェ(Guixe)ら、1998年;キー(Qi)およびグラボウスキー(Grabowski)、1998年)。
(4) 例えば標的から化合物(またはその逆)への蛍光共鳴エネルギー転移(FRET)が存在する可能性があり、その結果として励起が「ドナー」吸収波長にある場合「アクセプタ」発光波長での発光をもたらすといったように、結合時点で標的および化合物の両方の光学特性を修飾させる(ハイム(Heim)およびツィン(Tsien)、1996年;マハヤン(Mahajan)ら、1998年;宮脇ら、1997年)。
一変形実施形態においては、生化学プロセスを調節するように作用する化合物をスクリーニングするために本発明を使用することができる。化合物が標的の結合活性を活性化する場合、活性化される標的についてのリガンドを、当業者にとってなじみの深いさまざまな手段によりマイクロビーズに付着させることができる(例えば(ハーマンソン、1996年)を参照のこと)。反応の終りで、全てのマイクロカプセルは組合わされ、全てのマイクロビーズは1つの環境内で一緒にプールされる。所望の結合を示す化合物を担持するマイクロビーズを、標的に対し特異的に結合するかまたは標的と特異的に反応する分子を用いて親和性精製により選択することができる。
(1) リガンド自体は、独特の光学特性を有する可能性がある、例えば蛍光性である。
(2) 標的に対する結合時点でリガンドの光学特性を修飾させることができる、例えばリガンドの蛍光を結合時点で消光または増強させる(ヴォス(Voss)、1993年;増井(Masui)および倉光、1998年)。
(3) リガンドの結合時点で、標的の光学特性を修飾させることができる、例えば標的の蛍光を結合時点で消光または増強させる(ギシェ(Guixe)ら、1998年;キー(Qi)およびグラボウスキー(Grabowski)、1998年)。
(4) 結合時点で標的およびリガンドの両方の光学特性を修飾させる、例えば標的からリガンド(またはその逆)への蛍光共鳴エネルギー転移(FRET)が存在し得、その結果として励起が「ドナー」吸収波長にある場合「アクセプタ」発光波長での発光をもたらす(ハイム(Heim)およびツィン(Tsien)、1996年;マハヤン(Mahajan)ら、1998年;宮脇ら、1997年)。
一変形実施形態においては、本発明は所望の活性を有する化合物がマイクロカプセルの光学特性の変化を誘発し、かくして該化合物そして任意にはその中に含まれているマイクロビーズを同定し任意には選別できるようにする方法を提供している。マイクロカプセルの光学特性は、次のいずれかにより修飾可能である:
(1) グリコシダーゼ、ホスファターゼ、ペプチターゼおよびプロテアーゼのための基質を内含する、異なる光学特性をもつ調節された反応の生成物および基質(数多くの蛍光発生酵素基質が市販されている、例えば(ホーグランド(Haugland)、1996年およびwww.probes.com)を参照のこと)、または
(2) マイクロカプセル内の調節された反応の生成物(または基質)に対し特異的に結合するかまたはそれと特異的に反応し、かくしてマイクロカプセルの光学特性の変化を誘発しその同定を可能にする試薬の存在。
(1) 例えば
(a) グリコシダーゼ、ホスファターゼ、ペプチターゼおよびプロテアーゼのための基質を含む異なる光学特性をもつ基質および生成物(数多くの蛍光発生酵素基質が市販されている(例えばホーグランド、1996年およびwww.probes.com参照)または
(b) 類似の光学特性を有するものの、基質ではなく生成物のみがマイクロビーズに結合するかまたはこれと反応する、基質および生成物、
に起因して、基質−マイクロビーズ複合体の中には見られない特徴的光学特性を有する生成物−マイクロビーズ複合体、かまたは
(2) 生成物(基質)に対し特異的に結合するかまたはそれと特異的に反応しかくしてその同定を可能にするマイクロビーズの光学特性の変化を誘発する試薬を添加すること(マイクロカプセルの破壊およびマイクロビーズのプールの前後に、これらの試薬を添加できる)。試薬は、
(a) 基質および生成物の両方がマイクロビーズに付着している場合、生成物に対し特異的に結合するかまたはそれと特異的に反応するが、基質とはしない(またはその逆)
(b) 生成分のみがマイクロビーズに結合するかまたはこれと反応する場合、任意には基質と生成物の両方に結合する(またはその逆)。
ある種の標的について特異性および選択性を有するもののその他については有していない化合物は、1つの基質を用いた反応の調節のための正のスクリーンおよびもう1つの基質との反応の調節のための負のスクリーンを実施することにより、特異的に同定可能である。例えば、2つの異なる標的酵素に特異的な2つの基質が、各々異なる蛍光発生部分で標識される。各々の標的酵素は、2つの標的のための化合物の特異性に応じてマイクロカプセルの異なる光学特性を結果としてもたらす異なる蛍光スペクトルをもつ生成物の生成の触媒として作用する。
現行の薬物発見パラダイムにおいては、有効な組換え型標的がインビトロの高速大量処理スクリーニング(HTS)検定の基礎を成している。しかしながら単離されたタンパク質を、複雑な生体系を代表するものとみなすことはできない。従って、細胞ベースの系は、無傷の生体系の中での化合物活性に対する信頼性を高くすることができる。リード薬物のための広範囲の細胞ベースの検定が当業者にとって既知である。油中水型エマルジョンの微水滴といったようなマイクロカプセルに、細胞を区画化することができる(ガデシー(Ghadessy)、2001年)。標的に対する化合物の効果は、化合物と共にマイクロカプセルに細胞を区画化し、細胞に対する所望の効果をもつ化合物を含むこれらの区画を同定するために適切な細胞ベースの検定を用いることにより、判定可能である。フッ化炭素中水型エマルジョンの使用が特に有用であり得る。フッ化炭素の高いガス溶解能力は、呼吸ガスの交換を支援することができ、又、細胞培養系にとって有益であることが報告されている(ルーヴ(Lowe)、2002年)。
本発明の好ましい実施形態においては、マイクロカプセルまたはマイクロビーズは、フローサイトメトリーにより分析され、任意には選別される。マイクロカプセルの数多くのフォーマットがフローサイトメトリーを用いて分析され、任意には直接選別される。
(1) 定評のあるメーカー(例えばベクトン・ディッキンソン(Becton−Dickinson)、カルター(Coulter)、サイトメーション(Cytomation))製の蛍光活性化細胞選別装置は、毎秒最高100,000個のマイクロカプセルまたはマイクロビーズの速度での分析および選別を可能にする。
(2) 各々のマイクロカプセルまたはマイクロビーズからの蛍光シグナルは、存在する蛍光分子の数に密に対応する。マイクロカプセルまたはマイクロビーズ1個あたり数百個の蛍光分子という少量の分子を定量的に検出することができる。
(3) 蛍光検出器の広いダイナミックレンジ(標準的に4log単位)は、選別手順のストリンジェンシーを容易に設定できるようにし、かくして出発プールからの最適な数のマイクロカプセルまたはマイクロビーズの回収が可能となる(実施中の選択に応じて小さい蛍光差をもつマイクロカプセルまたはマイクロビーズを分離するかまたは大きな蛍光差をもつマイクロカプセルまたはマイクロビーズのみを分離するようにゲートを設定できる)。
(4) 蛍光活性化細胞選別装置は、多数の波長で同時励起および検出を実施することができ(シャピロ(Shapiro)、1995年)、2〜13個(またはそれ以上)の蛍光マーカーでのマイクロカプセルまたはマイクロビーズの標識を監視することにより正および負の選択を実施できるようにする。例えば、2つの交番標的のための基質が異なる蛍光タグで標識される場合、マイクロカプセルまたはマイクロビーズを、調節対象標的に応じて異なる蛍光プローブで標識することができる。
本発明は、利用中の選別技術によりそれが可能となっている場合には、無傷のマイクロカプセルの同定そして任意にはその選別を提供する。所望の化合物によって誘発された変化がマイクロカプセルの表面で発生するかまたは現われるかまたはマイクロカプセルの外側から検出可能である場合、マイクロカプセルを同定し、任意にそのように選別することができる。変化は、化合物の直接的作用によってひき起こされてもよいし、または、所望の活性をもつ化合物がそのうちの1つに関与している一連の反応がその変化を導く間接的作用によってひき起こされてもよい。例えば、マイクロカプセルが膜形成性マイクロカプセルである場合、そのマイクロカプセルは、標的を含む生化学系のコンポーネントがその表面で表示され、かくしてマイクロカプセル内部のマイクロビーズ上の化合物によって調節される生化学系の中の変化を検出し得る試薬にアクセス可能であるような形で構成され得る。
化合物ライブラリをさまざまな商業的供給源から得ることができる。ライブラリ内の化合物は、当業者にとって周知のさまざまな手段により作ることができる。任意には、1ビーズ−1化合物ライブラリを生成するべく、空間分解された並行合成または分割合成を用いて、組合せ合成により化合物ライブラリを作ることができる。該化合物は任意にはビーズ上で合成可能である。これらのビーズは、マイクロカプセルに直接区画化され得、そうでなければ化合物は区画化の前に放出される。
マイクロカプセル内またはマイクロビーズ上の化合物をさまざまな方法で同定することができる。同定されたマイクロカプセルが(例えば蛍光活性化細胞選別装置−FACSを使用することにより)選別される場合、化合物は例えば質量分析などの直接的分析によって同定可能である。化合物が(例えば親和性精製による)選択または(例えばFACSを用いた)選別の結果として単離されたビーズに付着した状態にとどまっている場合、それらは、同様に直接的分析例えば質量分析によっても同定され得る。マイクロカプセルまたはビーズは、当業者にとって周知のさまざまな手段および、ビーズに付着した化合物を同定するのに用いられるタグにより、タグ付けすることもできる(セザルニク(Czarnik)、1997年)。化合物をコード化するための化学的、分光的、電子的および物理的方法が全て使用可能である。好ましい実施形態においては、マイクロカプセルまたはビーズは異なる光学特性を有し、従って光学的にコード化される。好ましい実施形態においては、コード化は、異なる蛍光特性をもつマイクロカプセルまたはビーズに基づいている。きわめて好ましい実施形態においては、マイクロカプセルまたはビーズはその中に異なる濃度で存在する蛍光量子ドットを用いてコード化される(ハン、2001年)。マイクロ流体チャンネル内を整然とした順序で流れるマイクロカプセルは同様に、マイクロカプセル流内のそれらのシーケンスによっても(全体的にまたは部分的に)コード化され得る(位置的コード化)。
有利には、各々のマイクロカプセルが同じ標的の多重コピーを含むような形でマイクロカプセルに多数の異なる標的を区画化することができる。例えば、化合物の特異性を判定できるようにするため、多数のタンパク質キナーゼまたは単独の標的の多数の多型変種を区画化することができる。マイクロカプセル内の標的の同一性は、例えば上述の通りのマイクロカプセルまたはマイクロビーズの光学的コード化または位置的コード化によって判定され得る。
有利には、マイクロカプセルの融合後、融合されたマイクロカプセルの中に含まれた試薬は、カオス的移流を用いて急速に混合可能である。液滴内部の流体の層流線を分断するチャンネルの中に液滴を通過させることにより、その中味を迅速に混合し、あらゆる化学的反応を完全に開始させることができる。
本発明のある態様においては、流体液滴の1つ以上の特性を判定できるようにする形で、流体液滴の1つ以上の特性および/または該流体液滴を含む流体システム(例えば該流体液滴を取り囲む液体)の一部分の1特性を検知および/または判定できるセンサーが提供されている。液滴に関して判定可能でありかつ本発明において使用可能である特性は、当業者が同定可能である。かかる特性の制限的意味の無い例としては、蛍光、質量分析(例えば光学、赤外線、紫外線など)、放射能、質量、体積、密度、温度、粘度、pH生物学的物質(例えばタンパク質、核酸など)といった均質の濃度、などが含まれる。
本発明のマイクロ流体システムおよびデバイスの上述のコンポーネントのいずれかを形成するためには、本発明のある態様に従ってさまざまな材料および方法を使用することができる。一部のケースでは、選択されたさまざまな材料が、さまざまな方法に役立つ。例えば、本発明のさまざまなコンポーネントを固体材料で形成させることができ、ここでは、マイクロマシニング、スピンコーティングおよび化学蒸着といったような膜蒸着プロセス、レーザー製造、フォトリソグラフィ技術、湿式化学またはプラズマプロセスを含めたエッチング方法などを介してチャンネルを形成させることができる。例えばScientific American、第248号44〜55頁、1983年(エンジェル(Angell)、ら)を参照のこと。一実施形態においては、シリコンチップ内にフィーチャをエッチングすることにより、流体システムの少なくとも一部分がシリコンで形成される。シリコンを用いた本発明のさまざまな流体システムおよびデバイスの精確で効率の良い製造のための技術が知られている。もう1つの実施形態においては、本発明のシステムおよびデバイスのさまざまなコンポーネントが、例えばポリジメチルシロキサン(「PDMS」)、ポリテトラフルオロエチレン(「PTFE」またはTeflon(登録商標))などといったようなエラストマ重合体などの重合体で形成され得る。
マイクロ流体デバイスの概略的表示が、図15に示されている。マイクロチャンネルを、ポリ(ジメチルシロキサン)(PDMS)(マクドナルド(McDonald)およびホワイトサイズ、2002年)での高速プロトタイプ製造を用いて矩形断面を伴って製造し、(ソングおよびイスマギロフ(Ismagilov)、2003年)の通りに疎水性にした。フローを駆動するには、シリンジポンプを使用した(ハーバード・アパレイタス(Harvard Apparatus)PHD、2000還流ポンプ)。水溶液のためには、27ゲージの取外し可能な針のついた250μl入りのハミルトン・ガスタイト(Hamilton Gastight)シリンジ(1700シリーズ、TLL)を、30ゲージのテフロン管類(ウェイコ・ワイヤー・アンド・ケーブル(Weico Wire and Cable))と共に使用する。担体流体のためには、ハミルトン製の1つのハブ付き30ゲージのテフロン針(ソングおよびイスマギロフ、2003年)と共に、1ml入りのハミルトン・ガスタイトシリンジ(1700シリーズ、TLL)を使用する。担体流体は、ペルフルオロデカリン(PFD)中の9%(v/v)のC6F11C2H4OHである(ソングら、2003年)。マイクロ流体デバイスは、一連の相互接続されたモジュールから成る。各モジュールは、特定の機能を有する。これらのモジュールには、液滴を生成する、液滴を融合する、液滴を混合する、液滴を反応させる、液滴を検出するおよび液滴を選別するモジュールが含まれる(図16参照)。1つの実施例においては、異なる分子または異なる濃度の分子から成る液滴が作られる。液滴は最高104秒−1の速度で作られ、1.5%未満の多分散性および1μm〜100μmの範囲内のサイズで作られる。各々の液滴は第2組の反応物質を含む第2の液滴と融合され、急速に混合されて化学反応を開始する。この化学反応は、各液滴を遅延チャンネルの中で通過させることによって各液滴内で進行できるようになっている。次に各々の液滴は第2の組の反応物質を含むもう1つの液滴と融合され、その後第2の化学反応を開始させるべく急速に混合される。第2の反応が遅延モジュール内で進行した後、反応の結果は、光センサーまたはその他の形態の検出モジュールを用いて判定される。最終的に、所望の液滴は、光学検出モジュールからのシグナルに基づいて2つの集団内に選別され、一方の集団はさらなる処理のために保たれ、もう一方は廃棄される。これらのおよびその他のモジュールを、この組合せまたはその他の組合せで使用することができる。
マイクロ流体システム内のマイクロカプセルを用いたタンパク質チロシンホスファターゼ1B(PTP1B)阻害物質についてのスクリーニング
PTP1Bは、インシュリンおよびレプチンシグナル形質導入の負の調節因子である。インシュリンおよびレプチンに対する耐性は、2型真性糖尿病および肥満の特質であり、従ってPTP1Bは、糖尿病および肥満療法のための魅力的な薬物標的である(ジョンソン(Johnson)ら、2002年)。実施例1で記述されている通りのマイクロ流体デバイスを使用して、マイクロ流体システムの中でマイクロカプセルを用いていかにPTP1B阻害物質をスクリーニングできるかを記述する。
96の水性混合物を、(反応を防ぐため)氷上で作る。第1の混合物は、ビス−ジフルオロメチレンホスホナートを有しかつ既知のPTP1B阻害物質(ジョンソンら、2002年)である100μMの化合物2(図17)、および585nm、655nmおよび705nmの発光極大をもつ予め定義された比率のQdot(商標)ストレプトアビジンコンジュゲート(カンタム・ドット・コーポレーション(Quantum Dot Corporation)、Hayward、カリフォルニア州)を、PTP1B活性と相容性ある緩衝液(25mMのHEPES、pH7.4、125mMのNaCl、10%のグリセロール、1mMのEDTA)(ドマン(Doman)ら、2002年)中で含有している。95のその他の水性混合物は上述のものと同一であるが、各々化合物2の代りにカルボン酸有機ビルディングブロックライブラリ(アルドリッチ)からの95のカルボン酸のうちの1つおよび585nm、655nmおよび705nmの発光極大をもつ異なる比率のQdot(商標)ストレプトアビジンコンジュゲートを含有している。全ての混合物において、705nmQdot(商標)ストレプトアビジンコンジュゲートの濃度は100nMであり、585nmおよび655nmのQdot(商標)ストレプトアビジンコンジュゲートの濃度は、0、11、22、33、44、55、66、77、88または100nMのいずれかである。従って、Qdot(商標)ストレプトアビジンコンジュゲート濃度の100(10×10)個の順列が存在し、これが、各化合物を含有するマイクロカプセルに、705nm、585nmおよび655nmでの蛍光の蛍光比を判定することによって読取られる独特の蛍光サインをもたせることを可能にしている。
オレンジ色(585nm)および赤色(>650nm)の蛍光色素(フルトンら、1997年)を精確な比率で取込んだ結果として、表面上にカルボキシラート官能基を担持する直径5.5μmのポリスチレンマイクロビーズが光学タグ付けされた形で市販されている(www.luminexcorp.com)。各々独特の光学サイン(www.luminexcorp.com)をもつこのような100個のビーズのセットを余剰のエチレンジアミンおよびEDC(l−エチル−3−(3−ジメチルアミノプロピル)カルボジイミドヒドロクロリド(ピアース(Pierce)を用いて(ハーマンソン、1996年)の通りに修飾し、表面上に一級アミン基を作り上げる。該光開裂可能リンカー、4−(4−ヒドロキシメチル−2−メトキシ−5−ニトロフェノキシ)ブタン酸(ノバビオケム(NovaBiochem))(ホームズ(Holmes)およびジョーンズ(Jones)、1995年)を次に、上述のとおりEDCを用いてアミド結合を形成することによってビーズに付着させる。カルボン酸有機ビルディングブロックライブラリ(ブロック・ライブラリ(Block Library)(アルドリッチ))からの100個の異なるカルボン酸を次に、リンカーアルコールと反応させることによりビーズにカップリングさせて、カルボキシラートエステルを形成するが、ここで100個の異なる光学タグ付けされたビーズが異なるカルボン酸にカップリングされており、各ビーズは最高約106個のカルボン酸分子で誘導体化されている。最高5cmの距離からB100AP354nmのUV灯(UVP)を用いて氷上で4分間照射した結果、カルボン酸としてビーズから化合物が放出される。
オレンジ色(585nm)および赤色(>650nm)の蛍光色素(フルトンら、1997年)を精確な比率で取込んだ結果として、表面上にカルボキシラート官能基を担持する直径5.5μmのポリスチレンマイクロビーズが光学タグ付けされた形で市販されている(www.luminexcorp.com)。まず最初に、マイクロビーズ上のカルボキシラート官能基を、実施例6にある通り、エチレンジアミンおよびEDCを用いて一級アミンに転換させる。その後、PTP1Bのためのホスホペプチド基質、ウンデカペプチド(EGFR988−998(DADEpYLIPQQG)(チャン(Zhang)ら、1993年))を、EDCを用いて表面アミノ基を介してマイクロビーズの両方のセットにカップリングさせる。このペプチドは、カルボキシラート−O−アリルエステルを用いた側鎖カルボキシラート基上の直交保護を伴うSieberアミド樹脂((9−Fmoc−アミノ−キサンテン−3−イルオキシ−Merrifield樹脂)(ノバビオケム))上の固相合成によって作られる。テトラデカン二酸から成るリンカーをN−末端にカップリングし、1%のTFAを用いてビーズからペプチドを開裂させて、C末端アミドを伴うペプチドを生成する。リンカーを介して該ペプチドをビーズにカップリングし(EDCを用いて)、1ビードあたり最高105個のペプチドを得る。その後残った表面アミノ基を、実施例6にあるように光化学的に開裂可能なリンカー、4−(4−ヒドロキシメチル−2−メトキシ−5−ニトロフェノキシ)ブタン酸を付着させることによって修飾する。その後Pd(Ph3)4/CHCl3/HOAc/N−メチルモルホリンを用いて、ペプチドの側鎖カルボキシラート上の保護基を除去する。最初のマイクロビーズセットを、既知のPTP1B阻害物質である化合物3−(4−ジフルオロホスホノメチルフェニル)プロパン酸(化合物1、図17)、で誘導体化する(ジョンソンら、2002年)。第1のビーズセットとは相異なる光学タグを伴う第2のビーズセットを、PTP1B阻害物質でない化合物であるヒドロ桂皮酸(アルドリッチ)で誘導体化する。各々のケースにおいて、リンカーアルコールと反応させることによって化合物をカップリングして、実施例6にあるように、カルボキシラートエステルを形成させる。各々のマイクロビーズを、最高106個の分子(フルトンら、1997年)で誘導体化させる。
オレンジ色(585nm)および赤色(>650nm)の蛍光色素(フルトンら、1997年)を精確な比率で取込んだ結果として、各々独特の光学シグニチャーを伴う、表面上にカルボキシラート官能基を担持する直径5.5μmのポリスチレンマイクロビーズ100個のセット(www.luminexcorp.com)を、PTP1Bのためのホスホペプチド基質、ウンデカペプチドEGFR988−998(DADEpYLIPQQG)(チャンら、1993年)、および実施例4にあるように各々光化学的に開裂可能なリンカーを介して付着されている100個の異なるカルボン酸を用いて誘導体化する。これらのカルボン酸のうちの1つは、既知のPTP1B阻害物質である化合物(ジョンソンら、2002年)、3−(4−ジフルオロホスホノメチルフェニル)プロパン酸(化合物1、図17)である。その他の99のカルボン酸は、実施例4の通り、カルボン酸有機ビルディングブロックライブラリ(Carboxylic Acid Organic Building Block Library)(アルドリッチ)からのものである。次に、100ビーズセットの各々同数を、実施例5と同様に、混合し、スクリーニングする。主に、PTPIB阻害物質、3−(4−ジフルオロホスホノメチルフェニル)プロパン酸(化合物1、図17)でコーティングされたマイクロビーズ上でのみペプチドの脱リン酸化が見られ、その他の化合物でコーティングされたマイクロビーズ上には見られない。
基本的に(サトラーら、1996年)の通りに、14μmのフィルター(オスモニックス(Osmonics)を通した押出し(15回)によってかまたは5mmの分散工具と共にUltra−Turrax T8ホモジナイザー(IKA)を用いた25,000r.p.m.で5分間の均質化によって、95%(v/v)のペルフルオロオクチルプロミド、溶解状態の問題の分子を含む5%(v/v)のリン酸緩衝生理食塩水そして界面活性剤としての2%(w/v)のC8F17C11H22OP(O)[N(CH2CH2)2O]2(F8H11DMP)を含有するフッ化炭素中水エマルジョンを形成させた。100μmから2mMの濃度で水相中に溶解した一連の小さい蛍光分子を含有するエマルジョンを作った。カルセイン、テキサスレッド、フルオレセイン、クマリン102、7−ヒドロキシクマリン−3−カルボン酸および7−ジエチルアミノ−4−メチルクマリン(クマリン1)を含むこれらの分子は、SRCのLogKow/KowWinプログラム(メイラン(Meylan)およびハワード(Howard)、1995年)を用いて計算された−0.49〜4.09の範囲内のLogP値と203〜625Daの分子量を有していた。ボルテックス処理により、異なる色の蛍光色素を含むエマルジョンを混合した。混合型エマルジョンの落射蛍光顕微鏡法により区画化を観察した。混合後24時間、区画間に交換が全くないことを観察した(図19参照)。
基本的に、実施例1に記述されている通りに、多重液滴発生モジュールを用いて、95%(v/v)のペルフルオロオクチルプロミド、溶解状態の問題の分子を含む5%(v/v)のリン酸緩衝生理食塩水そして界面活性剤としての2%(w/v)のC8F17C11H22OP(O)[N(CH2CH2)2O]2(F8H11DMP)を含有するフッ化炭素中水エマルジョンを形成させた。各ノズルにおいて水相は、100μmから2mMの濃度で溶解した異なる小さな蛍光分子を含有していた。カルセイン、テキサスレッド、フルオレセイン、クマリン102、7−ヒドロキシクマリン−3−カルボン酸および7−ジエチルアミノ−4−メチルクマリン(クマリン1)を含むこれらの分子は、SRCのLogKow/KowWinプログラム(メイラン(Meylan)およびハワード(Howard)、1995年)を用いて計算された−0.49〜4.09の範囲内のLogP値と203〜625Daの分子量を有していた。全てのタイプの液滴を含有する単一の流れの中に異なるフルオロファーを有する液滴を担持する流れを組合わせることにより、異なる色の蛍光色素を含有するエマルジョンを混合した。液滴収集物を担持する流れはこのとき、デバイス上の深いウェル内に出され、ここで液滴は近接して保管され最高24時間にわたり監視可能である。液滴間の交差汚染は全く観察されない。
実施例1に記述されているとおりのマイクロ流体デバイスを用いて、我々は、フェニルエチルβ−D−チオガラクトピラノシド(PETG)による酵素、大腸菌□−ガラクトシダーゼ(LacZ)の阻害様式が競合的であることを実証し、いかにして、PETGの阻害定数(Ki)を得ることができるかを示している。酵素阻害検定においては、触媒作用速度は、LacZについての非蛍光性基質、フルオレセインモノ−□−D−ガラクトシド(FMG)(FMG)を使用し、蛍光性生成物フルオレセインの外観(励起488nm、発光514nm)を測定することによって決定される。LacZ阻害検定の全てのコンポーネントは、検定緩衝液(10mMのMgCl2、50mMのNaCl、1mMのDTT、100μg/mlのBSA、10mMのTris−HCl、pH7.9)の中で溶解させられる。
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Claims (115)
- 化合物レパートリ内の所望の活性を有する1つ以上の化合物を同定するための方法であって、
a) 前記レパートリの1サブセットのみが、任意のマイクロカプセル内において多重コピーで代表されるような形で、前記化合物をマイクロカプセルに区画化する工程;および
b) 前記所望の活性を有する前記化合物を同定する工程、
を含み、工程a)およびb)のうちの一方または両方がマイクロ流体制御下で実施される方法。 - 工程a)が、個々の化合物を含むマイクロカプセルのグループを形成する工程および前記マイクロカプセルグループを混合して乳化化合物レパートリを形成する工程を含み、ここで前記レパートリのサブセットが任意の1マイクロカプセル内において多重コピーで代表されている、請求項1に記載の方法。
- 工程(a)が、
i. 前記レパートリの1サブセットのみが任意の1マイクロビーズ内で表わされるような形で、前記化合物レパートリをマイクロビーズ上に付着させる工程および
ii. 前記マイクロビーズをマイクロカプセルに区画化する工程、
を含み、かくして、前記レパートリの1サブセットが任意の1マイクロカプセル内において多重コピーで代表されるようになっており、工程i)およびii)の一方または両方がマイクロ流体制御下で実施される、請求項1に記載の方法。 - 前記所望の活性が、結合活性および標的の前記活性の変調からなる群から選択される、請求項1に記載の方法。
- 前記結合活性が標的に対する結合である、請求項4に記載の方法。
- 前記変調された活性が結合活性である、請求項4に記載の方法。
- 前記変調された活性が触媒活性である、請求項4に記載の方法。
- 前記化合物が標的と反応して反応生成物を生成する、請求項1に記載の方法。
- 前記化合物が開裂不可能なリンカーを介してマイクロビーズにカップリングされている、請求項3に記載の方法。
- 前記化合物が開裂可能なリンカーを介してマイクロビーズにカップリングされる、請求項3に記載の方法。
- 前記化合物が、光化学開裂可能なリンカーを介してマイクロビーズにカップリングされる、請求項10に記載の方法。
- 前記化合物が、開裂可能なリンカーおよび開裂不能なリンカーの組合せによりマイクロビーズにカップリングされる、請求項3に記載の方法。
- 前記標的が前記化合物と共にマイクロカプセル中に区画化されている、請求項4に記載の方法。
- 所望の活性を有する前記化合物が、それが会合されている前記マイクロビーズまたはマイクロカプセル内で、該マイクロビーズまたはマイクロカプセルの同定、選別または選択を可能にする変化を起こす、請求項1に記載の方法。
- 前記化合物がマイクロビーズに結合され、前記マイクロカプセル内の前記所望の活性が、前記マイクロビーズの単離を可能にするべく前記化合物が付着しているマイクロビーズを直接的または間接的に修飾することになる、請求項14に記載の方法。
- 前記標的が前記マイクロビーズに結合させられており、前記マイクロカプセル内の前記所望の活性を有する前記化合物が、前記マイクロビーズの前記単離を可能にするべく前記標的に対し直接的または間接的に結合する、請求項15に記載の方法。
- 前記マイクロビーズが親和性精製によって単離される、請求項15または16に記載の方法。
- 基質が前記マイクロカプセル内に存在し、前記マイクロカプセル内の前記化合物の前記所望の活性が、前記基質の生成物への転換を直接的または間接的に調節することになる、請求項7に記載の方法。
- 前記基質が、前記標的の触媒作用により前記生成物へと転換される、請求項18に記載の方法。
- 前記基質および前記生成物が異なる光学特性を有する、請求項18または19に記載の方法。
- 前記基質および前記生成物が異なる蛍光特性を有する、請求項20に記載の方法。
- 前記基質が前記マイクロビーズに結合させられており、前記マイクロカプセル内の前記化合物の前記所望の活性が、前記マイクロビーズの一部としてとどまってその同定および任意にはその単離を可能にする生成物への前記基質の転換を直接的または間接的に調節することになる、請求項18に記載の方法。
- 前記生成物そして任意には前記未反応基質がその後前記マイクロカプセル内で前記マイクロビーズと複合体化させられる、請求項18に記載の方法。
- 前記所望の活性が、基質から生成物への前記転換を増強させる、請求項18に記載の方法。
- 前記所望の活性が、基質から生成物への転換を阻害する、請求項18に記載の方法。
- 前記マイクロカプセル内の前記化合物の前記所望の活性が、その後前記マイクロビーズと複合体化されその単離を可能にする生成物を直接的または間接的に生成する、請求項7に記載の方法。
- 所望の活性を有する前記化合物が、前記マイクロカプセルの同定、選別または選択を可能にする前記マイクロカプセル内の変化を起こす、請求項1に記載の方法。
- 前記マイクロカプセル内の前記化合物の前記所望の活性が、前記マイクロカプセルの前記光学特性の変化を誘発する、請求項1に記載の方法。
- 前記マイクロカプセルが、その蛍光の変化を検出することによって同定される、請求項28に記載の方法。
- 前記蛍光の変化が、蛍光共鳴エネルギー転移(FRET)に起因する、請求項29に記載の方法。
- マイクロカプセル内の前記化合物が、前記マイクロカプセルの前記光学特性の差異により同定される、請求項28に記載の方法。
- 前記マイクロカプセルの前記光学特性の前記差異が蛍光の差異である、請求項31に記載の方法。
- 前記マイクロカプセルの前記蛍光の前記差異が、量子ドットの存在に起因する、請求項32に記載の方法。
- 前記化合物が、異なる濃度で異なるマイクロカプセル内に存在する、請求項1に記載の方法。
- マイクロカプセル内の前記化合物の前記濃度が、前記マイクロカプセルの前記光学特性の差異により同定される、請求項34に記載の方法。
- 前記マイクロカプセルの前記光学特性の前記差異が蛍光の差異である、請求項35に記載の方法。
- 前記マイクロカプセルの前記蛍光の前記差異が、量子ドットの存在に起因する、請求項36に記載の方法。
- マイクロカプセル内の前記標的が、前記マイクロカプセルの前記光学特性の差異により同定される、請求項28に記載の方法。
- 前記マイクロカプセルの前記光学特性の前記差異が蛍光の差異である、請求項38に記載の方法。
- 前記マイクロカプセルの前記蛍光の前記差異が、量子ドットの存在に起因する、請求項39に記載の方法。
- 前記マイクロビーズの前記修飾には、その光学特性の変化が含まれる、請求項15に記載の方法。
- 前記マイクロビーズの前記光学特性の前記差異が蛍光の差異である、請求項41に記載の方法。
- マイクロビーズ上の前記化合物が、前記マイクロビーズの前記光学特性の差異により同定される、請求項41に記載の方法。
- 前記マイクロビーズの前記光学特性の前記差異が蛍光の差異である、請求項43に記載の方法。
- 前記マイクロビーズの前記蛍光の前記差異が、量子ドットの存在に起因する、請求項44に記載の方法。
- 前記マイクロビーズが非磁性、磁性または常磁性である、請求項3に記載の方法。
- 前記マイクロビーズがその蛍光変化の検出により選別される、請求項42に記載の方法。
- 前記マイクロビーズ同定が、フローサイトメトリーによるものである、請求項47に記載の方法。
- 前記マイクロビーズ選別が、蛍光活性化細胞選別装置(FACS)を用いて実施される、請求項47に記載の方法。
- 前記蛍光変化が、蛍光共鳴エネルギー転移(FRET)に起因する、請求項47に記載の方法。
- 前記マイクロビーズの前記修飾によりマイクロビーズは前記マイクロカプセルの外側でさらに修飾されてその光学特性の変化を誘発できる、請求項42に記載の方法。
- 前記マイクロビーズの光学特性の前記変化が、独特の光学特性をもつ化合物の前記マイクロビーズに対する結合に起因する、請求項42に記載の方法。
- 前記マイクロビーズの光学特性の前記変化が、前記化合物による独特の光学特性をもつ標的の結合に起因する、請求項42または43に記載の方法。
- 前記マイクロビーズの光学特性の前記変化が、標的に結合した場合の前記化合物の前記光学特性の変化に起因する、請求項42または43に記載の方法。
- 前記マイクロビーズの光学特性の前記変化が、前記化合物により結合された場合の前記標的の前記光学特性の変化に起因する、請求項42または43に記載の方法。
- 前記マイクロビーズの光学特性の前記変化が、結合時点での標的および化合物の両方の前記光学特性の変化に起因する、請求項42または43に記載の方法。
- 前記所望の活性をもつ前記化合物が前記標的内で変化を起こすように作用し、前記マイクロビーズの光学特性の前記変化が、前記標的に対する前記化合物の前記作用の前記生成物と前記標的の光学特性が異なることに起因する、請求項42または43に記載の方法。
- 前記所望の活性をもつ前記化合物が、その光学特性を改変することなく前記標的内で変化を起こすように作用するが、前記標的ではなく前記作用の前記生成物のみが、前記マイクロビーズに結合するかまたはそれと反応し、かくして前記マイクロビーズの前記光学特性を変化させる、請求項42または43に記載の方法。
- さらなる試薬が、前記マイクロビーズに付着している前記調節された反応の前記生成物(前記基質ではない)に特異的に結合するかまたはこれと特異的に反応し、かくして前記マイクロビーズの前記光学特性を改変させる、請求項42または43に記載の方法。
- さらなる試薬が、前記マイクロビーズに付着している前記調節された反応の前記基質(前記生成物ではない)に特異的に結合するかまたはこれと特異的に反応し、かくして前記マイクロビーズの前記光学特性を改変させる、請求項42または43に記載の方法。
- 化合物の非所望活性が前記所望の活性の結果として得られるものとは異なる前記マイクロビーズまたは前記マイクロカプセルの変化を結果としてもたらす、請求項1に記載の方法。
- 前記非所望活性の結果としてもたらされる前記変化が、前記マイクロカプセルまたは前記マイクロビーズの負の選択のために使用される、請求項61に記載の方法。
- 負の選択が、反応の特異性を改善するべく正の選択と組合わされる、請求項62に記載の方法。
- 前記改善された反応特異性が、結合特異性の改善である、請求項63に記載の方法。
- 前記改善された反応特異性が、前記標的についての領域および/または立体選択性の改善である、請求項64に記載の方法。
- 前記所望の化合物の活性によって直接的または間接的に修飾されたマイクロビーズがチラミドシグナル増幅(Tyramido Signal Amplification(TSA(商標);NEN)によってさらに修飾され、その結果、前記マイクロビーズの光学特性の変化を直接的または間接的にもたらし、かくしてその同定および任意には単離が可能となる、請求項42に記載の方法。
- 各々のマイクロビーズまたはマイクロカプセルが2つ以上の化合物を含み、かつ各々の化合物が前記マイクロビーズまたは前記マイクロカプセルが選択され得るように所望の活性を有していなければならない、請求項1に記載の方法。
- 前記1つ以上の化合物が低分子量化合物である、請求項1に記載の方法。
- 前記レパートリの前記サブセットが単一の化合物である、請求項1に記載の方法。
- 各々のマイクロカプセルまたはマイクロビーズが、単一の化合物の多重分子をそれに会合された状態で有している、請求項69に記載の方法。
- 工程(a)〜(b)のうちの1つ以上のものを反復的に繰り返す工程をさらに含む、請求項1に記載の方法。
- マイクロカプセル化が油中水エマルジョンを形成することによって達成される、請求項1に記載の方法。
- 前記油中水エマルジョンがマイクロ流体システムを用いて作られる、請求項72に記載の方法。
- 前記エマルジョンが、非混和液の同時フロー蒸気の中の水滴中断により形成される、請求項73に記載の方法。
- 前記エマルジョンが、第2の流体により取り囲まれた第1の流体を電荷に付すことによって形成される、請求項73に記載の方法。
- マイクロカプセルが、マイクロ流体チャンネル内で流体の流れの中の層流によって輸送されている、請求項1に記載の方法。
- 前記マイクロカプセルが、マイクロ流体チャンネル内で油の流れの中に分散された微水滴である、請求項76に記載の方法。
- マイクロカプセル内の前記化合物が、マイクロ流体チャンネル内のその他のマイクロ液滴に比べた前記マイクロカプセルの相対的位置により同定される、請求項76に記載の方法。
- マイクロカプセル内の化合物の前記濃度が、マイクロ流体チャンネル内のその他のマイクロ液滴に比べた前記マイクロカプセルの前記相対的位置により同定される、請求項76に記載の方法。
- マイクロカプセル内の前記標的が、マイクロ流体チャンネル内のその他のマイクロ液滴に比べた前記マイクロカプセルの相対的位置により同定される、請求項76に記載の方法。
- 前記同定されたマイクロカプセルがマイクロ流体デバイスを用いて選別される、請求項1に記載の方法。
- 同定されたマイクロカプセルの前記選別が、電場を用いて荷電マイクロカプセルを操縦することによってマイクロ流体流選別デバイスを用いて達成される、請求項81に記載の方法。
- 前記マイクロ流体デバイスには、前記マイクロ流体チャンネル内で前記マイクロカプセルが発出するシグナルを検出するセンサーが具備されている、請求項82に記載の方法。
- マイクロカプセルがマイクロ流体デバイスを用いて融合または分割される、請求項1に記載の方法。
- マイクロカプセルが電場を加えることによって分割される、請求項84に記載の方法。
- 第1および第2のマイクロカプセルが、それに対して相対する電荷を印加することによって融合される、請求項84に記載の方法。
- マイクロカプセルが、該マイクロカプセルを合体させる内部の双極子の誘発により融合される、請求項84に記載の方法。
- フッ化炭素中水またはペルフルオロカーボン中水エマルジョンを形成することによってマイクロカプセル化が達成される、請求項72に記載の方法。
- 前記フッ化炭素が臭化ペルフルオロオクチルまたはペルフルオロオクチルエタンである、請求項88に記載の方法。
- 前記エマルジョンがF−アルキルジモルホリノホスファートを用いて形成される、請求項88に記載の方法。
- 前記F−アルキルジモルホリノホスファートが一般構造式CnF2n+1CmH2mOP(O)[N(CH2CH2)2O]2を有する、請求項90に記載の方法。
- 前記F−アルキルジモルホリノホスファートがC8F17C11H22OP(O)[N(CH2CH2)2O]2である、請求項91に記載の方法。
- 前記マイクロカプセルの前記内部環境が、前記油相に対し1つ以上の試薬を添加することによって修飾される、請求項1に記載の方法。
- 前記化合物が、異なる光学特性をもつビーズにカップリングされている、請求項3に記載の方法。
- 前記ビーズが異なる蛍光特性を有する、請求項94に記載の方法。
- 前記ビーズの前記異なる光学特性が、前記ビーズ内への異なるレベルの2つ以上の蛍光色素の取込みに起因している、請求項94に記載の方法。
- 前記ビーズの前記異なる光学特性が、異なる発光スペクトルをもつ異なる数の量子ドットの取り込みに起因している、請求項94に記載の方法。
- 前記ビーズの前記異なる光学特性が、ビーズに結合した前記化合物を同定するために使用される、請求項94に記載の方法。
- 前記単離されたビーズ上の前記化合物が、前記ビーズからの前記化合物の放出および直接的分析によって同定される請求項15または16に記載の方法。
- 単離されたビーズ上の化合物が質量分析によって同定される、請求項99に記載の方法。
- 化合物の調製方法であって、
(a) 前記レパートリの1サブセットのみが、任意の1マイクロカプセル内において多重コピーとして示されるように、前記化合物をマイクロカプセルに区画化する工程;
(b) 前記所望の活性を有する前記化合物を同定する工程;および
(c) 前記所望の活性を有する前記化合物を同定し生産する工程、
を含み、工程a、bおよびcのうちの1つ以上のものがマイクロ流体制御下で実施される、方法。 - 化合物の調製方法であって
(a) 前記レパートリの1サブセットのみが、任意の1マイクロカプセル内において多重コピーとして示されるように、前記化合物をマイクロカプセルに区画化する工程;
(b) その光学特性の変化を用いて前記所望の活性を有する前記化合物を含有する前記マイクロカプセルを同定しかつ任意にはそれを選別する工程;および
(c) 前記所望の活性を有する前記化合物を同定し生産する工程、
を含む方法。 - 標的の前記活性を変調させる能力をもつ1つ以上の化合物をスクリーニングする方法であって、
(a) 前記レパートリの1サブセットのみが、任意の1マイクロカプセル内において多重コピーとして示されるように、前記化合物をマイクロカプセルに区画化する工程;
(b) その光学特性の変化を用いて前記所望の活性を有する前記化合物を含有する前記マイクロカプセルを同定しかつ任意にはそれを選別する工程;および
(c) 1つ以上の化合物と所望の活性をもつ標的を接触させ、前記1つ以上の化合物による前記標的の活性の前記変調を監視する工程
を含み、工程a、bおよびcのうちの1つ以上のものがマイクロ流体制御下で実施される、方法。 - 標的を調製する方法であって、
(a) 少なくとも1つの工程が化合物によって容易になる、標的用合成プロトコルを提供する工程;
(b) この工程を容易にする前記化合物の変種を調製する工程;
(c) 前記レパートリの1サブセットのみが、任意の1マイクロカプセル内において多重コピーとして示されるように、前記化合物をマイクロカプセルに区画化する工程;
(d) その光学特性の変化を用いて前記所望の活性を有する前記化合物を含有する前記マイクロカプセルを同定しかつ任意にはそれを選別する工程;および
(e) 前記合成の関連工程を容易にするべく(d)で同定された前記化合物を使用して前記標的を調製する工程、
を含み、工程a〜eのうちの1つ以上のものがマイクロ流体制御下で実施される、方法。 - 前記化合物がマイクロビーズに付着され、前記化合物が任意には前記マイクロカプセル内部の前記マイクロビーズから放出される、請求項102〜105のいずれか1項に記載の方法。
- 化合物および標的が最初、その後融合される異なるマイクロカプセルの中にある請求項13に記載の方法。
- 化合物および標的を含むマイクロカプセルが、前記標的上の前記化合物の前記所望の活性を検出するのに必要とされる1つ以上の分子を含むマイクロカプセルと融合される、請求項13に記載の方法。
- 化合物を含むマイクロカプセルの前記融合の結果得られた前記マイクロカプセルが、標的を含むマイクロカプセルと融合させられ、その後、前記標的上の前記化合物の前記所望の活性を検出するのに必要とされる1つ以上の分子を含むマイクロカプセルと融合させられる、請求項13または106に記載の方法。
- 前記標的上の前記化合物の前記所望の活性を検出するために必要とされる1つ以上の前記分子が、酵素基質である、請求項107に記載の方法。
- 前記基質が前記標的用の基質である、請求項109に記載の方法。
- 化合物を含むマイクロカプセルが分割されて2つ以上のマイクロカプセルを生成する、請求項1に記載の方法。
- 標的を含むマイクロカプセルが分割されて2つ以上のマイクロカプセルを生成する、請求項13に記載の方法。
- 1つ以上の細胞が、マイクロカプセル内にある、請求項1に記載の方法。
- 前記化合物が前記細胞内の標的の前記活性を変調させる、請求項113に記載の方法。
- 前記化合物が、前記細胞の活性を変調させる、請求項114に記載の方法。
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EP3527978A3 (en) | 2019-09-25 |
US20170102381A1 (en) | 2017-04-13 |
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AU2005293367A1 (en) | 2006-04-20 |
CA2582465A1 (en) | 2006-04-20 |
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EP3153231A1 (en) | 2017-04-12 |
EP3153231B1 (en) | 2019-03-13 |
EP2602018B1 (en) | 2016-04-27 |
WO2006040551A3 (en) | 2006-06-29 |
JP4829240B2 (ja) | 2011-12-07 |
US20190317085A1 (en) | 2019-10-17 |
US10705078B2 (en) | 2020-07-07 |
EP3527978A2 (en) | 2019-08-21 |
US10371699B2 (en) | 2019-08-06 |
EP1842067B1 (en) | 2016-12-14 |
EP2602018A1 (en) | 2013-06-12 |
US20200333334A1 (en) | 2020-10-22 |
US20050221339A1 (en) | 2005-10-06 |
US9498759B2 (en) | 2016-11-22 |
WO2006040551A2 (en) | 2006-04-20 |
CA2582465C (en) | 2014-09-16 |
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